Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970""s.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin xcex1), and neurokinin B (also known as neuromedin K and neurokinin xcex2). See, J. E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see, e.g., S. L. Shepheard, et al., British Journal of Pharmacology, 108.11-20 (1993); S. M. Moussaoui, et al., European Journal of Pharmacology, 238:421-424 (1993); and W. S. Lee, et al., British Journal of Pharmacology, 112:920-924 (1994).
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in U.S. Pat. No. 5,491,140, issued Feb. 13, 1996; U.S. Pat. No. 5,328,927, issued Jul. 12, 1994; U.S. Pat. No. 5,360,820, issued Nov. 1, 1994; U.S. Pat. No. 5,344,830, issued Sep. 6, 1994; U.S. Pat. No. 5,331,089, issued Jul. 19, 1994; European Patent Publication 591,040 A1, published Apr. 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published Jan. 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published Mar. 3, 1994; Patent Cooperation Treaty publication WO 93/011609, published Jan. 21, 1993; Canadian Patent Application 2154116, published Jan. 23, 1996; European Patent Publication 693,489, published Jan. 24, 1996; and Canadian Patent Application 2151116, published Dec. 11, 1995.
U.S. Pat. No. 5,530,009, issued Jun. 25, 1996, describes a 1,2-diacylaminopropane for use in treating conditions associated with an excess of tachykinins. This patent also teaches processes for preparing this compound.
In essence, this invention provides a class of potent non-peptidyl tachykinin receptor antagonists similar to those of U.S. Pat. No. 5,530,009. By virtue of their non-peptidyl nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
This invention provides novel compounds of Formula I 
wherein:
R1 and R2 are independently hydrogen, halo, C1-C6 alkyl, hydroxy, or C1-C6 alkoxy;
R5, R6, and R7, are independently hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, or hydroxy;
R3 is hydrogen, C2-C7 alkanoyl, glycyl, or dimethylglycyl;
n is 1-6;
D is xe2x80x94S(O)mxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94Oxe2x80x94,
m is 0, 1, or 2; and
R8 is a monocyclic or bicyclic carbocyclic or heterocyclic group, optionally substituted with one or more moieties selected from the group consisting of oxo, C1-6 alkyl, C1-C6 alkoxy, hydroxy, halo, and trifluoromethyl;
or a pharmaceutically acceptable salt or solvate thereof
In another embodiment this invention provides methods of treating a condition associated with an excess of tachykinins, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof
This invention also provides pharmaceutical formulations comprising, as an active ingredient, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients therefor.
The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cNxe2x80x9d refers to normal or normality; xe2x80x9cmolxe2x80x9d refers to mole or moles; xe2x80x9cmmolxe2x80x9d refers to millimole or millimoles; xe2x80x9cgxe2x80x9d refers to gram or grams; xe2x80x9ckgxe2x80x9d refers to kilogram or kilograms; xe2x80x9cLxe2x80x9d refers to liter or liters; xe2x80x9cmlxe2x80x9d means milliliter or milliliters; xe2x80x9cMxe2x80x9d refers to molar or molarity; xe2x80x9cMSxe2x80x9d refers to mass spectrometry; and xe2x80x9cNMRxe2x80x9d refers to nuclear magnetic resonance spectroscopy.
xe2x80x9cC1-C6 alkoxyxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term xe2x80x9cC1-C6 alkoxyxe2x80x9d includes within its definition the terms xe2x80x9cC1-C4 alkoxyxe2x80x9d and xe2x80x9cC1-C3 alkoxyxe2x80x9d.
As used herein, the term xe2x80x9cC1-C12 alkylxe2x80x9d refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term xe2x80x9cC1-C12 alkylxe2x80x9d includes within its definition the terms xe2x80x9cC1-6 alkylxe2x80x9d and xe2x80x9cC1-C4 alkylxe2x80x9d.
xe2x80x9cC2-C7 alkanoyloxyxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms attached to a carbonyl moiety joined through an oxygen atom. Typical C2-C7 alkanoyloxy groups include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like.
xe2x80x9cC3-C8 cycloalkylxe2x80x9d represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms. Typical C3-C8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
xe2x80x9cHaloxe2x80x9d represents chloro, fluoro, bromo or iodo.
xe2x80x9cC1-C6 alkylthioxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical C1-C6 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.
xe2x80x9cC1-C12 alkylenylxe2x80x9d refers to a straight or branched, divalent, saturated aliphatic chain of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl. The term xe2x80x9cC1-C6 alkylenylxe2x80x9d is encompassed within the term xe2x80x9cC1-C12 alkylenylxe2x80x9d.
xe2x80x9cC1-C10 alkylaminoxe2x80x9d represents a group of the formula
xe2x80x94NH(C1-C10 alkyl)
wherein a chain having from one to ten carbon atoms is attached to an amino group. Typical C1-C4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.
xe2x80x9cC1-C6 alkylaminoxe2x80x9d represents a straight or branched alkylamino chain having from one to six carbon atoms attached to an amino group. Typical C1-C6 alkyl-amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like. xe2x80x9cC1-C6 alkylaminoxe2x80x9d encompasses within this term xe2x80x9cC1-C4 alkylaminoxe2x80x9d.
xe2x80x9cC2-C6 alkanoylxe2x80x9d represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety. Typical C2-C6 alkanoyl groups include ethanoyl (acetyl), propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.
xe2x80x9cC2-C7 alkoxycarbonylxe2x80x9d represents a straight or branched alkoxy chain having from one to six carbon atoms attached to a carbonyl moiety. Typical C2-C7 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.
The term xe2x80x9ccarbamoylxe2x80x9d as used herein refers to a moiety having one of the following structures. 
The term xe2x80x9cC2-C7 alkylcarbamoylxe2x80x9d as used herein refers to a branched or unbranched chain of 1 to 6 carbon atoms combined with a carbamoyl group, as such is defined above. This moiety has the following structure. 
The term xe2x80x9chaloformatexe2x80x9d as used herein refers to an ester of a haloformic acid, this compound having the formula 
wherein X is halo, and Rd is C1-C6 alkyl. Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein Rd is C3-C6 alkyl are especially preferred. Most preferred is isobutylchloroformate.
The compounds prepared in the processes of the present invention have an asymmetric center. As a consequence of this chiral center, the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
In addition to the (R)xe2x80x94(S) system, the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix xe2x80x9cDxe2x80x9d is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and xe2x80x9cLxe2x80x9d, that of the isomer in which it is on the left.
The term xe2x80x9camino-protecting groupxe2x80x9d as used in the specification refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include formyl, trityl (herein abbreviated as xe2x80x9cTrxe2x80x9d), phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl (herein abbreviated as xe2x80x9cBOCxe2x80x9d), 1,1-diphenylether-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy-carbonyl (xe2x80x9cFMOCxe2x80x9d), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups. Preferred amino-protecting groups are trityl, t-butoxycarbonyl (t-BOC), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, (J. G. W. McOmie, ed., 1973), at Chapter 2; and T. W. Greene and P. G. M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991), at Chapter 7.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used in the specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while reacting other functional groups on the compound. Examples of such carboxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2xe2x80x2,4,4xe2x80x2-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferred carboxy-protecting groups are allyl, benzyl and t-butyl. Further examples of these groups are found in E. Haslam, supra, at Chapter 5, and T. W. Greene, et al., supra, at Chapter 5.
The term xe2x80x9chydroxy-protecting groupsxe2x80x9d as used herein refers to substitents of the hydroxy group commonly employed to block or protect the hydroxy functionality while reacting other functional groups on the compound. Examples of such hydroxy-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2,2-dichloro-1,1-difluoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, C1-C6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl. Further examples of these groups may be found in T. W. Greene and P. G. M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991) at Chapter 3.
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term xe2x80x9cleaving groupxe2x80x9d as used in this document encompasses, but is not limited to, activating groups.
The term xe2x80x9cactivating groupxe2x80x9d as used herein refers a leaving group which, when taken with the carbonyl (xe2x80x94Cxe2x95x90O) group to which it is attached, is more likely to take part in an acylation reaction than would be the case if the group were not present, as in the free acid. Such activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or xe2x80x94Oxe2x80x94COxe2x80x94(C4-C7 alkyl).
As noted supra, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Salts of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formulas I. Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
This invention also encompasses the pharmaceutically acceptable prodrugs of the compounds of Formula I. A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. This prodrug should have a different pharmacokinetic profile than the parent, enabling easier absorption across the mucosal epithelium, better salt formation or solubility, or improved systemic stability (an increase in plasma half-life, for example).
Typically, such chemical modifications include:
1) ester or amide derivatives which may be cleaved by esterases or lipases;
2) peptides which may be recognized by specific or nonspecific proteases; or
3) derivatives that accumulate at a site of action through membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, DESIGN OF PRODRUGS, (1985).
The compounds of Formula I are generally prepared by reacting a compound of Formula II 
with an appropriately substituted carboxylic acid, anhydride, or carboxylic acid halide in the presence of typical peptide coupling reagents such as N,Nxe2x80x2-carbonyldiimidazole (CDI), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). A polymer supported form of EDC has been described (Tetrahedron Letters, 34(48):7685 (1993)) and is very useful for the preparation of the compounds of the present invention. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. The product from these reactions may be purified chromatographically or recrystallized from a suitable solvent if desired.
Another preferred method of preparing the compounds of Formula I where D is xe2x80x94Oxe2x80x94 is by reacting a compound of Formula III 
where X is a leaving group, preferably a halo moiety, most preferably a bromo group, with an appropriately substituted phenol, naphthol, or the like.
The most preferred method, to date, of synthesizing the intermediates of Formulae II and III is depicted in Scheme I, infra. Many of the steps of this synthesis are described in Patent Cooperation Treaty Publication WO 95/14017, published May 26, 1995; European Patent Application Publication 693,489, published Jan. 24, 1996; and U.S. Pat. No. 5,530,009, issued Jun. 25, 1996, the entire contents of which are herein incorporated by reference. 
In another method of preparing the intermediates of Formulae II and III, Steps a) and b) can be combined as taught in U.S. patent application Ser. No. 60/021,849, filed Jul. 16, 1996. In this method a compound of the formula 
is prepared by reacting a compound of the formula 
with bis(trimethylsilyl)amine in acetonitrile, followed by the addition of trityl chloride, N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine, in the presence of acetonitrile, and then adding 2-methoxybenzylamine.
The factor eventually found critical to the combination of the steps was the desilylation of the compound of Formula A, in Step (a), prior to ester formation via the addition of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). In Step (a), desilylation had been accomplished by the addition of excess water prior to isolation which also dissolved any salts present. When desilylating Formula A in the combined chemistry, stoichiometry becomes increasingly important. Consideration must be given to the presence of excess HMDS used in the initial silylation of D-tryptophan. Simply adding a stoichiometric amount of methyl alcohol (or water) relative to D-tryptophan will not allow the subsequent esterification to progress. Methyl alcohol must also be added to quench all remaining unreacted HMDS. However, any excess methyl alcohol will consume CDMT and prevent complete esterification. Once the desilylation of the compound of Formula A and decomposition of excess HMDS is complete, the chemistry of Step (b) proceeds as expected and high quality desired intermediate is produced in good yield.
In the above process, the intermediate amides are reduced to amines using procedures well known in the art. These reductions can be performed using lithium aluminum hydride as well as by use of many other different aluminum-based hydrides. An especially preferred reagent employed in this reduction is RED-AL(copyright), which is the tradename of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. Alternatively, the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usually required for this. Sodium borohydride in combination with other reagents may be used to reduce the amide. Borane complexes, such as a borane dimethylsulfide complex, are especially useful in this reduction reaction.
The acylation of the secondary amine can be done using any of a large number of techniques regularly employed by those skilled in organic chemistry. One such reaction scheme is a substitution using,an anhydride such as acetic anhydride. Another reaction scheme often employed to acylate a secondary amine employs a carboxylic acid preferably with an activating agent. An amino-de-alkoxylation type of reaction uses esters as a means of acylating the amine. Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents. One preferred such activated ester is p-nitrophenyl ester, such as p-nitrophenyl acetate.
Primary amines can also be acylated using amides to perform what is essentially an exchange reaction. This reaction is usually carried out with the salt of the amine. Boron trifluoride, usually in the form of a boron trifluoride diethyl ether complex, is frequently added to this reaction to complex with the leaving ammonia.
An additional step is one of substitution of the secondary amine. For most of the compounds of Formula I this substitution is one of alkylation, acylation, or sulfonation. This substitution is usually accomplished using well recognized means. Typically, alkylations can be achieved using alkyl halides and the like as well as the well-known reductive alkylation methods, employing aldehydes or ketones. Many of the acylating reaction protocols discussed supra efficiently acylate the secondary amine as well. Alkyl- and aryl-sulfonyl chlorides can be employed to sulfonate the secondary amine.
In many instances one of the later steps in the synthesis of the compounds of Formulae II and III is the removal of an amino- or carboxy-protecting group. Such procedures, which vary, depending upon the type of protecting group employed as well as the relative lability of other moieties on the compound, are described in detail in many standard references works such as T. W. Greene, et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991).